Lung cancer accounts for more deaths than any other cancer in both men and women. An estimated 159,260 deaths, accounting for about 27% of all cancer deaths, are expected to occur in the United States in 2014 (American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society, 2014). Lung cancer is broadly classified into two types: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer (NSCLC) comprises 80-85% of lung cancer cases in the United States. NSCLC comprises three major types: (i) Squamous cell carcinoma, which begins in squamous cells, that are thin, flat cells that look like fish scales. Squamous cell carcinoma is also called epidermoid carcinoma; (ii) Large cell carcinoma, which begins in several types of large lung cells; (iii) Adenocarminoma, which begins in the cells that line the alveoli of the lung and make substances such as mucus. Other less common types of NSCLC include pleomorphic carcinoma, carcinoid tumor and unclassified carcinoma.
Poly(ADP-ribose)polymerse (PARP) or poly(ADP-ribose)synthase (PARS) is a nuclear enzyme that has an essential role in recognizing DNA damage, facilitating DNA repair, controlling RNA transcription, mediating cell death, and regulating immune response. PARP activity is required for the repair of single-stranded DNA breaks through the base excision repair pathways. Cancer cells are often deficient in double-stranded DNA-repair capability, and are therefore more dependent on PARP directed single-stranded DNA-repair than are normal cells. Consequently, inhibition of PARP enhances the anti-tumor effects of DNA-damaging agents in many cancer cells.
Platinum-based chemotherapy regimens are the current standard of care for subjects with metastatic or advanced non-small cell lung cancer (NSCLC). Veliparib (ABT-888, 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide) is a potent, orally bioavailable PARP inhibitor that enhances the efficacy of platinum-containing DNA damaging therapies in some pre-clinical models, and veliparib has been safely combined with full dose carboplatin and paclitaxel in human clinical trials. The present invention describes the use of veliparib in combination with carboplatin and paclitaxel in the treatment of smokers with non-small cell lung cancer.